Viral Hepatitis: State of the Art

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  • HCV was first recognized as a separate entity in 1975 after it was determined that the majority of cases of transfusion-related hepatitis were not caused by the 2 types of hepatitis recognized at the time (hepatitis A and B). The disease was called “non-A non-B” hepatitis until the virus was cloned and sequenced in 1989. At that time the virus was renamed hepatitis C virus. HCV is a linear single-strand RNA virus 40-50 nanometers in size that belongs to the Flaviviridae family and the Hepacivirus genus. The virus is covered with a lipid envelope and is encased with glycoprotein peplomers or “spikes.” www.hephet.com/nih/purcell.html www.clevelandclinicmeded.com/diseasemanagement/gastro/hepatitis_c/hepatitis_c.htm www.hepcprimer.com
  • Hepatitis C: A Global Health Problem According to CDC estimates, approximately 3-4 million people in the US are currently infected with the hepatitis C virus (see map). There are, however, a few distinct geographic regions where infection is especially common. In Egypt, for example, HCV infection occurs in 10% to 30% of the general population. Likewise, the prevalence of infection is greater than 10% in certain parts of Asia and high rates of infection have been found in certain geographic regions of Japan, Taiwan, and Italy. In such areas, HCV infection is generally more prevalent among persons over the age of 40 and uncommon under the age of 20. This cohort effect suggests that transmission probably occurred through a practice that has been discontinued, such as traditional folk remedies or reuse of needles for injection. In developing countries, nosocomial transmission is most likely the principal route of HCV infection. Evidence from Egypt, Romania, and other nations, before economic transition, point to various percutaneous practices performed in the context of traditional and nontraditional medical care. The incidence of acute hepatitis C in the US has decreased during the last decade, from approximately 180,000 cases per year to approximately 30,000 to 50,000 cases per year. References Cohen J. The scientific challenge of hepatitis C. Science. 1999;285(5424):26-27. Alter MJ. Epidemiology of Hepatitis C. Hepatology . 1997;26(suppl 1):62S-65S. World Health Organization. Weekly epidemiological report. 1999;74:421-428. Available at: http://www.who.int/wer/pdf/1999/wer7449.pdf. Accessed February 19, 2003.
  • Lecture Notes HCV is the most common chronic bloodborne infection. In the United States, 3.9 million people have been infected, or 1.8% of the population. Of these, 2.7 million are chronically infected. 1 The number of new infections, however, has declined by 80% in the past decade, to 36,000 in 1996. 2 The decline in incidence of new infections is largely attributed to improved safety of the blood supply, and to needle exchange programs. The long delay, however, between infection and liver disease, coupled with the large number of individuals who are already infected, suggests that the impact of HCV will continue to grow before reaching a peak. The medical and economic impact of hepatitis C in the United States is considerable and expected to grow during the next 2 to 3 decades. Hepatitis C causes 40% of all chronic liver disease in the United States 2 and is the leading reason for liver transplantation. Hepatitis C accounts for 8000 to 10,000 deaths per year 2 and HCV-related mortality may double over the next 10 to 20 years. 3 References 1. Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med . 1999;341:556-562. 2. Centers for Disease Control and Prevention. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR . 1998;47(RR-19):1-39. 3. Wong JB, McQuillan GM, McHutchison JG, Poynard T. Estimating future hepatitis C morbidity, mortality, and costs in the United States. Am J Public Health . 2000;90:1562-1569.
  • Prevalence of HCV Infection US 1990 Data from the Third National Health and Nutrition Examination (NHANES III), conducted between 1988 to 1994, have indicated that the prevalence of HCV infection was higher among non-Hispanic blacks than among non-Hispanic whites and higher among male subjects than among female subjects. In all racial-ethnic groups, the prevalence of infection was low among subjects in the younger and older age groups, although among non-Hispanic blacks prevalence began to increase at an earlier age (12 to 19 years) than in the other groups. The delayed peak in prevalence among Mexican Americans 50 to 59 years old was probably attributable to the small numbers of subjects and may not accurately reflect the true prevalence of this group. The highest observed prevalence was 6.3% among African-Americans who were 40-49 years of age; African American males had an observed prevalence rate of 9.8%. Note that under the age of 12, the rate of hepatitis infection is less than 1%. This relates to either vertical transmission or to those who acquired infection by past transfusions. Increased risk during the teen years probably relates more to the use of illegal drugs than the initiation of sexual activity. Within the Caucasian population, risk falls dramatically for people in their fifties. Reference 1.Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States. 1988-1994. N Engl J Med. 1999;341:556-562.
  • Lecture Notes Approximately 60% of cases of hepatitis C are due to injection drug use. Fifteen percent of cases may be sexually transmitted. Ten percent of cases are due to transfusion-related infections. Unknown sources account for approximately 10% of cases and nosocomial, occupational, and perinatal exposure together account for another 5%. 1 Reference 1. CDC. Hepatitis C Slide set. Available at: http://www.cdc.gov/ncidod/diseases/hepatitis/slideset. September 25, 2000. Accessed: February 5, 2002.
  • Lecture Notes A number of risk factors for HCV have been identified. Patients who have any of these identified risk factors should be tested for HCV antibodies. This includes patients who received blood from any donor who later tested positive for HCV, a blood transfusion or solid organ transplant before July 1992, or a blood product for clotting problems produced before 1987. Also included are patients who have ever injected illegal drugs or used intranasal cocaine or been on long-term kidney dialysis, patients with persistently abnormal alanine aminotransaminase (ALT) levels or a high-risk sexual history, and patients who are HIV-positive.
  • Key Points Shiffman et al (2000) demonstrated the histologic variability in two subsets of HCV infected patients: In patients with elevated ALTs, there was some degree of histologic impairment in 71% of the patients. Most significantly, 22% of the patients had cirrhosis, while 16% had evidence of bridging. In patients with normal ALTs, there was some degree of histologic impairment in 60% of the patients. When compared with the elevated ALT group, the difference in rates of cirrhosis and bridging were appreciable. The normal ALT patient group had a 6% rate of cirrhosis (elevated ALT: 22%) and a 6% rate of bridging (elevated ALT: 16%). References Shiffman ML, Stewart CA, Hofmann CM, et al. Chronic infection with hepatitis C virus in patients with elevated or persistently normal serum alanine aminotransferase levels: comparison of hepatic histology and response to interferon therapy. J Infect Dis . 2000;182:1595-1601.
  • Lecture Notes The hepatitis C virus is classified into six genotypes, with >90 serotypes, based on genetic differences. Genotypes 1a and 1b are the most common in the United States, accounting for about two thirds of all cases. HCV genotype can be predictive of outcome to therapy, as genotypes 2 and 3 are more responsive to treatment 1 and are typically treated with just 24 weeks of therapy, rather than 48 weeks. Reference 1. McHutchison JG, Gordon SC, Schiff ER, et al, for the Hepatitis Interventional Therapy Group. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med . 1998;339:1485-1492.
  • Type 1 IFNs: exhibit multiple activities Type 1 IFNs have a large number of biological actions; most of these actions involve the immune system. IFN induction, early innate immune response, provides a priming mechanism that influences many subsequent innate and adaptive immune responses. For example, type 1 IFNs can activate natural killer cells and increase T lymphocyte survival The primary action of type 1 IFNs is an antiviral effect. IFNs can inhibit viral replication at one of several sites and by one of several mechanisms, including at entry and/or uncoating, during replication, by influencing RNA stability, during the initiation of translation, or at maturation, assembly, or release. Type 1 IFNs also have antiproliferative, antifibrotic, antiangiogenic biologic actions References Stark GR, Kerr IM, Williams BR, et al. How cells respond to interferons. Annu Rev Biochem. 1998;67:227-264. Theofilopoulos AN, Baccala R, Beutler B, et al. Type I interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol . 2005;23:307-335. Brierley MM, Fish EN. IFN-alpha/beta receptor interactions to biologic outcomes: understanding the circuitry. J Interferon Cytokine Res. 2002;22:835-845.
  • This slides illustrates viral kinetics during treatment with IFN-based therapy. The slope of viral load decline is biphasic. After a lag period of 4 to 12 hours, there is a rapid decline in viral load. This first phase is characterized by a block of virion production or release with the effect being dose dependent. A 10 million unit/day dose produces a significantly faster first-phase decline than does a 5 million unit/day dose and the slope of this curve is predictive for achieving sustained virologic response. The slope of the second phase is less steep and is determined by the rate of infected cell clearance. Ribavirin works in synergy with IFN with the effects primarily on the second phase decline. This enhancement in the second phase means than the addition of ribavirin to patients with slower rates of virus decline (eg, difficult-to-treat patients such a African Americans and those with genotype 1) may help to increase the rate of complete viral clearance. Neumann AU, Lam NP, Dahari H, et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science. 1998;282:103-107. Dixit NM, Layden-Almer JE, Layden TJ, Perelson AS. Modelling how ribavirin improves interferon response rates in hepatitis C virus infection. Nature. 2004;432:922-924.
  • Lecture Notes Approximately 85% of infected individuals will develop chronic hepatitis. Of these, 20% to 50% will progress to develop cirrhosis. One quarter of those with cirrhosis will progress to hepatic decompensation and 1% to 4% will progress to hepatocellular carcinoma. This progression typically takes place over the course of 20 to 30 years.
  • Key Points Age older than 40 years, male gender, and consumption of alcohol are significant risk factors for fibrosis progression. An immunocompromised state, occurring secondary to HIV or HBV infection, also increases the risk for progression. It is possible, as well, that the use of injectable heroine may speed development of fibrosis. Objective : To assess the natural history of liver fibrosis progression in patients with hepatitis C and determine the factors associated with this progression. Methods : Treatment-naïve patients with documented HCV and at least 1 liver biopsy were enrolled in the study. Fibrosis progression was defined as the ratio between fibrosis stage in METAVIR units and duration of infection. A 2-step process was used to identify factors associated with progression: analysis between progression and 9 risk factors, and analysis of the association between fibrosis stage and the risk factors. Results : A total of 2235 subjects participated in the study; among those for whom the duration of infection was known(1157), the mean rate of fibrosis progression was 0.252 (median, 0.133). The mean duration from infection to cirrhosis was 30 years. A highly statistically significant ( P <.0001) association was identified between stage of fibrosis and age at biopsy and duration of infection. Risk factors associated with fibrosis progression included consumption of alcohol daily ( P <.001), male gender ( P <.001), and infection occurring at age 40 years or older ( P <.001). Factors that were not associated with risk for progression were cause of infection, genotype, and viremia. Conclusion : Host factors—age, male gender, and alcohol consumption—have a stronger relationship with risk for fibrosis progression than virologic factors. Immunosuppression secondary to HIV co-infection and HBV, also increases the risk for progression, perhaps through immune dysfunction and/or direct cytotoxicity. References Hezode C, et al. Daily smoking of cannabis is a risk factor for fibrosis progression in persons with chronic hepatitis C. Presented at: 39 th European Association for the Study of Liver Diseases; April 14-18, 2004; Berlin, Germany. Abstract 68. Ivanova I, et al. Intravenous drug abuse may accelerate liver fibrosis progression in chronic hepatitis C. Presented at: 39 th European Association for the Study of Liver Diseases; April 14-18, 2004; Berlin, Germany. Abstract 484. National Institutes of Health Consensus Development Conference Statement. Management of hepatitis C: 2002. Bethesda, Md: National Institutes of Health; June 10-12, 2002. Poynard T, Bedrossa P, Opolon P, for the OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC group. Natural history of liver fibrosis progression in patients with chronic hepatitis C. Lancet . 1997;349:825-832.
  • Lecture Notes The liver transplant wait list is steadily increasing. Cirrhosis due to HCV infection is the reason for >50% of liver transplants. 1 Currently, more than 19,000 patients are awaiting liver transplantation, yet there are only approximately 4900 livers available each year. Therefore, without intervention, the majority of patients who have end-stage liver disease due to hepatitis C will die of it while waiting for transplant. Reference 1. United Network for Organ Sharing (UNOS). 2000 T & OPTN Annual Report. Available at: www.unos.org. Accessed: January 9, 2002.
  • Key Points In contrast to older age at acquisition of HCV, male gender, and consumption of alcohol, fibrosis progression was not associated with viremia, genotype, mode of transmission, or ALT levels. Genotype, including genotype 1b, and high versus low viremia showed no association with fibrosis progression. This lack of association remained when comparing by age strata. Of those infected with HCV 1b genotype, the rate of fibrosis was higher in patients over 40 years of age than in the younger patients. There was no significant difference in stage of fibrosis between HCV genotypes, including 1b versus other genotypes. Regarding viremia, the investigators point out that these observations were determined by comparison with biopsy samples for 50% of the subjects and the sample size was small. Thus, they urge cautious interpretation of the lack of an association between viremia and fibrosis progression. Alanine aminotransferase (ALT) is only weakly correlated with disease severity and ALT levels are insensitive for detecting disease progression. References National Institutes of Health Consensus Development Conference Statement. Management of hepatitis C: 2002. Bethesda, Md: National Institutes of Health; June 10-12, 2002. Poynard T, Bedrossa P, Opolon P, for the OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC group. Lancet . 1997;349:825-832.
  • Utility of Liver Biopsy In the last 50 years, use of the liver biopsy has grown to serve multiple purposes: (1) confirmation of clinical diagnosis, (2) assessment of severity of necroinflammation and fibrosis, (3) evaluation of possible concomitant disease processes, and (4) assessment of therapeutic intervention. Liver biopsy remains the best method for assessing the severity of hepatitis C however remains controversial. For many clinicians, the histologic appearance of the liver substantially influences the decision of whom to treat and whether to continue treatment in patients with non-life threatening adverse reactions. The findings may also serve as a baseline in establishing extent of liver damage and determining the prognosis. Although the current guidelines for use of biopsy are controversial, as therapy becomes more successful and safer, it is likely that HCV-infected persons will routinely be started on therapy without biopsy. If necessary, patient may be referred to a radiologist for the liver biopsy. Reference Brunt E. Grading and staging the histopathological lesions of chronic hepatitis: the Knodell histology activity index and beyond. Hepatology. 2000;31:241-246.
  • Hepatic Histopathologic Evaluation Since publication of the Knodell HAI, systems for grading and staging incorporate the view that the grade (necroinflammation) is not only a measure of severity but also of ongoing disease activity and the parameter most potentially responsive to therapy.The grade may fluctuate with disease activity or therapeutic intervention. The lesions of fibrosis and parenchymal or vascular remodeling are referred to as “stage” and indicate long-term disease progression. The stage is considered relatively constant. A variety of systems for grading and staging are available, but they may arrive at a score using different criteria. Hence, it is important to know what classification is being used. For example, stage 4 in the METAVIR system is cirrhosis while in the Ishak system stage 4 is extensive bridging fibrosis but not cirrhosis (incomplete or complete). Reference Brunt E. Grading and staging the histopathological lesions of chronic hepatitis: the Knodell histology activity index and beyond. Hepatology. 2000;31:241-246.
  • Progression of Fibrosis on Biopsy Key Points Pictured on this slide are hepatic histologic samples, depicting the various stages of cirrhosis. The normal liver is pictured first, followed by: Stage 1 with fibrous expansion of some portal areas Stage 3 with fibrous expansion of most portal areas with occasional portal to portal bridging Stage 4 with fibrous expansion of portal areas with marked bridging (portal to portal and portal to central) Stage 6 with cirrhosis, probable, or defined The final picture is a cirrhosed liver removed during autopsy.
  • Hepatic Fibrosis Scoring Systems Since publication of the Knodell HAI, various systems to measure the severity of ongoing liver disease have been implemented to simplify the process. All systems report stage and grade, although they may arrive at a score using different criteria. The differences are subtle but potentially important when comparing clinical studies that have used 2 different systems. Ishak’s 1994 review promoted the use of descriptive terminology for activity and fibrosis, rating the different elements of activity as either present or absent; when present a degree of severity is stated. The recent modification of the Knodell HAI, commonly referred to as the Ishak system, provides consecutive scores for well-defined lesions within 4 separate categories that are added together for the activity grade. The lower end of the fibrosis scale (0-2) reflects the fact that not all portal tracts show similar amounts of portal and periportal fibrosis, and the assigned score is not based on the most advanced lesion but rather on the lesion affecting some or most of the portal tracts. Reference Brunt E. Grading and staging the histopathological lesions of chronic hepatitis: the Knodell histology activity index and beyond. Hepatology. 2000;31:241-246.
  • Rates of fibrosis progression This slide illustrates that the rates of fibrosis progression may vary depending on the patient characteristics. For example, men aged >40 years who consume more than 50 g/day of alcohol are much more likely to experience a rapid rate of fibrosis progression. In contrast, women who are infected before the age of 40 and who are nondrinkers or consume <50 g/day of alcohol, are likely to display a slow rate of fibrosis progression. Reference Marcellin P, Asselah T, Boyer N. Fibrosis and disease progression in hepatitis C. Hepatology. 2002;36:S47-S56.
  • Key Points The primary goals of HCV therapy are aimed at clearing the virus and targeting liver disease. The 3 key objectives in management of liver disease are delayed decompensation, prevention of hepatocellular carcinoma, and prevention of recurrent infection in post liver transplantation patients.
  • In summary, nonresponders can be identified at weeks 12, 24, and 48. Relapsers can be identified at week 72. These are the important time points for HCV RNA testing
  • This slide illustrates the approved and available agents for the treatment of HCV. Standard interferons (eg, IFN alfa-2a, IFN alfa-2b, IFN alfacon-1) were the first agents available. These agents are administered in three times weekly regimens. IFN alfacon-1 or consensus IFN (CIFN), at a higher dose, is also approved for the treatment of patients who do not respond to or who relapse after prior IFN treatment. Pegylated interferons (PEG-IFNs) have the advantage of a more convenient dosage schedule (once weekly). Oral ribavirin is added to IFN as part of a combination regimen to improve response rates. The FDA-approved dosing of ribavirin is 0.8 – 1.2 g/day divided BID. Pawlotsky JM, McHutchison JG. Hepatitis C. Development of new drugs and clinical trials: promises and pitfalls. Summary of an AASLD hepatitis single topic conference, Chicago, IL, February 27-March 1, 2003. Hepatology. 2004;39:554-567.
  • SVR rates in HCV populations This graph illustrates sustained virologic response (SVR) rates achieved with pegylated interferon (PEG-IFN) plus ribavirin (RBV) after 48 weeks of treatment. Overall, large randomized trials have demonstrated that this regimen produces an SVR in slightly over 50% of all patients. However, the rates of SVR are lower in certain difficult-to-treat populations, such as those with genotype 1 (41%-44%), high viral load (HVL) [all genotypes] (42%-53%), and advanced fibrosis and cirrhosis [Stages 3 and 4] (43%-44%). In addition, those with hepatitis C virus/human immunodeficiency virus (HCV/HIV) coinfection have a lower rate of SVR (27%-40%), especially coinfected patients with genotype 1 (17%-29%). African Americans with genotype 1 have among the lowest rates of SVR (19%-26%). References Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med. 2004;351:438-450. Jeffers LJ, Cassidy W, Howell CD, et al. Peginterferon alfa-2a (40 kd) and ribavirin for black American patients with chronic HCV genotype 1. Hepatology. 2004;39:1702-1708. Carrat F, Bani-Sadr F, Pol S, et al. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA. 2004;292:2839-2848. Muir AJ, Bornstein JD, Killenberg PG; Atlantic Coast Hepatitis Treatment Group. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med. 2004;350:2265-2271. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.
  • Manns : A SVR rate of 41% has been achieved with IFN alfa-2b plus RBV therapy of chronic HCV. In this randomised trial, PEG IFN alfa-2b plus RBV was compared with IFN alfa-2b plus RBV. 1530 patients with chronic HCV were assigned IFN alfa-2b (3 MU SC TIW) plus RBV 1000-1200 mg/day orally, PEG IFN alfa-2b 1.5 µg/kg each week plus 800 mg/day RBV, or PEG IFN alfa-2b 1.5 µg/kg QW for 4 weeks then 0.5 µg/kg per week plus RBV 1000-1200 mg/day for 48 weeks. The primary endpoint was the SVR rate (undetectable HCV RNA in serum at 24-week follow-up). Analyses were based on patients who received at least one dose of study medication. Exclusion criteria: decompensated cirrhosis, elevated serum AFP, transplant, other causes of liver disease, preexisting psychiatric disease, seizure disorders, CVD, hematologic alterations, hemophilia, poorly controlled DM, autoimmune disease, inability to use contraception. Fried : Researchers compared the efficacy and safety of PEG IFN alfa-2a plus RBV, IFN alfa-2b plus RBV, and PEG IFN alfa-2a alone in the initial treatment of chronic hepatitis C. A total of 1121 patients were randomly assigned to treatment and received at least one dose of study medication, consisting of 180 µg of PEG IFN alfa-2a QW plus daily RBV (1000 or 1200 mg, depending on body weight), weekly PEG IFN alfa-2a plus daily placebo, or 3 MU IFN alfa-2b TIW plus QD RBV for 48 weeks. Exclusion criteria: neutropenia, thrombocytopenia, anemia, HIV, decompensated liver disease, elevated serum creatinine, poorly controlled psychiatric disease, alcohol or drug dependence within one year before entry into trial, substantial coexisting medical conditions. Hadziyannis : A total of 1311 patients at 99 sites in 21 countries were randomized and given treatment as follows: Group A: PEG IFN alfa-2a 180 µg QW plus RBV 800 mg daily for 24 weeks (n = 214) Group B: PEG IFN alfa-2a 180 µg QW plus RBV 1000-1200 mg daily for 24 weeks (n = 288) Group C: PEG IFN alfa-2a 180 µg QW plus RBV 800 mg daily for 48 weeks (n = 365) Group D: PEG IFN alfa-2a 180 µg QW plus RBV 1000-1200 mg daily for 48 weeks (n = 444) All patients were followed up for 24 weeks after discontinuing treatment. Patients were further stratified by HCV genotype (1 vs. non-1) and viral load (low vs high, defined as < or  2 million copies/mL, respectively, and by geographical region. Treatment duration was blinded until week 24; dose of RBV blinded throughout the study. Exclusion criteria: neutropenia, thrombocytopenia, anemia, seizure disorders, HAV, HBV, HIV, decompensated liver disease, elevated serum creatinine, malignant neoplastic disease, poorly controlled psychiatric disease, alcohol or drug dependence within one year before entry into trial, substantial coexisting medical conditions. References Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med . 2002;347:975-982. Hadziyannis SJ, Sette H Jr, Morgan TR, Balan V, Diago M, Marcellin P, et al; PEGASYS International Study Group. Peginterferon-{alpha}2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140:346-355. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.
  • Lecture Notes Results from the peginterferon alfa-2/ribavirin clinical trial demonstrated that 1.5 µg/kg peginterferon alfa-2b plus 800 mg ribavirin combination therapy was significantly more effective than standard-dose interferon alfa-2b/ribavirin ( P = .01). 1 This combination produced the highest ETVR (62%) and SVR (54%) observed to date in the treatment of chronic HCV infection. The increase was attributable to decreases in the rates of breakthrough infections and relapse. The low-dose arm—0.5 µg/kg peginterferon alfa-2b/ribavirin—produced response rates equivalent to standard interferon alfa-2b/ribavirin, while still allowing for the convenience of once-weekly interferon dosing. 1 Response to peginterferon alfa-2b/ribavirin combination therapy varied by HCV genotype 1 : Patients with genotype 1 had lower SVR rates than did patients with genotype 2/3, which is consistent with trials of nonpegylated interferon/ribavirin. 2,3 Thus, genotype is still a primary predictive factor for treatment outcome. However, the best response to therapy in genotype 1–infected patients was produced with 1.5 µg/kg peginterferon alfa-2b/ribavirin, which resulted in SVR rates of 42% versus 33% with standard combination therapy ( P = .02). As expected, the highest response rates were observed in patients with HCV genotype 2/3 infections. The SVR was 82% with 1.5 µg/kg peginterferon alfa-2b/ribavirin, indicating that the vast majority of these patients can achieve long-term viral eradication. 1 Note also that the FDA approval for peginterferon alfa-2b cites a 52% SVR for 1.5 µg/kg peginterferon alfa-2b/ribavirin, not 54% as reported by Manns et al. 1 This is because the FDA excluded the results of several patients in their analysis of these data. Reference 1. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.
  • Lecture Notes Peginterferon alfa-2a plus ribavirin is currently under investigation and has not been approved by the FDA. In a large clinical trial by Fried et al 1 , peginterferon alfa-2a plus ribavirin demonstrated results similar to that of peginterferon alfa-2b plus ribavirin. Patients receiving peginterferon alfa-2a plus ribavirin achieved an SVR rate of 56%, compared with 30% for those receiving peginterferon alfa-2a plus placebo and 45% for those receiving standard interferon alfa-2b plus ribavirin. In patients infected with genotype 1, peginterferon alfa-2a plus ribavirin demonstrated a higher SVR (46%) than either peginterferon alfa-2a plus placebo (37%, P = .016) or standard interferon alfa-2b plus ribavirin (21%, P = .001). 1 In patients with genotypes 2 or 3, peginterferon alfa-2a plus ribavirin produced an SVR of 76%, compared with 61% for peginterferon alfa-2a plus placebo ( P = .008) and 45% for standard interferon alfa-2b plus ribavirin ( P = .001). The treatments were well tolerated, and no major safety concerns were noted. Note that ribavirin doses used in this trial were higher (1000-1200 mg/d) than those used in the high-dose arm of the peginterferon alfa-2b/ribavirin trial (800 mg/d). Reference 1. Fried M, Shiffman ML, Reddy RK, et al. Pegylated (40kDa) interferon alfa-2a (PEGASYS ® ) in combination with ribavirin: efficacy and safety results from a phase III, randomized actively- controlled, multicenter study [abstract 289]. Gastroenterology . 2001;120:(suppl):A-55.
  • HVC is composed of a single-stranded RNA genome approximately 9.6 kilobases long that encodes a single, large polyprotein of about 3,000 amino acids. This polyprotein is cleaved post-translationally into multiple structural and nonstructural (NS) peptides. The structural peptides include a nucleocapsid core (C), 2 envelope glycoproteins (E1, E2), and a calcium channel (p7). The NS proteins are labeled NS2 through NS5. Although the specific functions of the NS proteins have not been completely characterized, their presumed functions are illustrated in the slide. In particular, the highly conserved NS3 and NS5 segments of the genome contain structured RNA elements that are vital for the initiation of protein translation (both NS3 and NS5) and for RNA transcription (NS3). These structures represent potential attractive targets for anti-HCV therapy. Hoofnagle JH. Course and outcome of hepatitis C. Hepatology. 2002;36:S21-S29. Pawlotsky JM, McHutchison JG. Hepatitis C. Development of new drugs and clinical trials: promises and pitfalls. Summary of an AASLD hepatitis single topic conference, Chicago, IL, February 27-March 1, 2003. Hepatology. 2004;39:554-567.
  • Key Points Listed above are the primary side effects of IFN therapy, as identified and confirmed in numerous clinical studies.
  • Key Points Ribavirin therapy is associated with certain side effects, including Hemolytic anemia Teratogenicity Cough and dyspnea Rash and pruritus Insomnia Anorexia Combination IFN/RBV therapy, however, has been found to be relatively safe and consistent with the safety profile of each agent when used alone. Use of the 2 agents in combination is not believed to result in an increase of adverse effects. References Maddrey WC. Safety of combination interferon alfa-2b/ribavirin therapy in chronic hepatitis C-relapsed and treatment naïve patients. Semin Liver Dis. 1999;19(suppl 1):74. Rebetron  [package insert]. Kenilworth, NJ: Schering Corp; 1999.
  • Key Points A number of pretreatment variables are predictive of a response to IFN therapy. Combination therapy—IFN/RBV or PEG IFN/RBV combination therapy demonstrates higher SVR rates in patients infected with HCV therapy 48-week duration—48 weeks of therapy demonstrates higher SVR rates, particularly in the more difficult to treat genotype 1 patients Genotype 2 or 3—24 weeks of therapy may emerge as the duration of therapy for patients with genotypes 2 and 3. These non-1 genotypes are associated with higher SVR rates and may require lower doses of RBV. Data presented at EASL 2004 demonstrates Gt 3 is more difficult to cure than Gt 2. Low baseline viral load—clinical studies are determining SVR rates are higher in patients with baseline viral loads < 2 x 10 6 copies/mL Absence of portal fibrosis Female—female gender is associated with better SVR Aged < 40 years—age at time of transmission of virus has an association with SVR rate Low hepatic iron stores—higher hepatic iron stores are associated with lower SVR rates Short duration of disease (<5 years)—patients with shorter duration of disease have higher SVR rates References Davis GL, Nelson DR, Reyes GR, et al. Future options for the management of hepatitis C. Hepatology. 1997;26 (suppl 1):122S-127S. Hadziyannis SJ, Sette H Jr, Morgan TR, Balan V, Diago M, Marcellin P, et al; PEGASYS International Study Group. Peginterferon-{alpha}2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140:346-355. Mangia A, Minerva N, Ricci GL, et al. HCV genotype 2 and 3 can be cured by peg-IFN-2B and RBV for 12 wks: A randomized controlled study. Program and abstracts of the 39th Annual Meeting of The European Association for the Study of the Liver; April 14-18, 2004; Berlin, Germany. Abstract 93. Poynard T, McHutchison J, Goodman Z, et al. Is an a la carte combination IFN alfa-2b plus RBV regimen possible for the first line treatment in patients with chronic hepatitis C? Hepatology . 2000;31:211-218. Zeuzem S, Feinman V, Rasenack J, et al. Peginterferon alfa-2a in patients with chronic hepatitis. N Engl J Med . 2000;342:1666-1672.
  • HBV Vaccination Program in the US Hepatitis B vaccine has been available in the United States since the early 1980s. In 1982 the vaccine was recommended for adults and adolescents with significant risk factors. In 1991, the Immunization Practices Advisory Committee of the CDC recommended that all newborn infants be vaccinated. This was followed by revised guidelines from the American Academy of Pediatrics to recommend that all infants be immunized against hepatitis B. Additionally, all pregnant women were to be screened, and post-exposure prophylaxis was to be administered to infants born to infected mothers to prevent perinatal HBV infection. In 1995, revised CDC guidelines called for the immunization of all adolescents aged 11-12 years in an effort to further protect children against the hepatitis B virus. In 1999, the strategy was expanded to include all persons 0-18 years of age who had not been previously vaccinated. HBV Treatments in the US Although there is still no cure for hepatitis B, there are 5 approved drugs for adults (2 for children) as follows: Intron A (interferon- α ) is given by injection, several times a week for six months to a year, or sometimes longer. Approved in 1991 and indicated for both children and adults. Pegylated Interferon (Pegasys) is given by injection once a week usually for six months to a year. Approved May 2005 and indicated only for adults. Epivir-HBV, (lamivudine) is a tablet that is taken once a day, for at least one year or longer. Approved in 1998 and indicated for both children and adults. Hepsera (adefovir dipivoxil) is a tablet taken once a day for at least one year or longer. Approved September, 2002 and indicated only for adults. Pediatric clinical trials are being planned. BARACLUDE (entecavir) is supplied as tablets and oral solution, taken once a day. Approved March 2005 and indicated only for adults sixteen years of age and older. References: MMWR. 2004;52:1252-1254. HepB.Org. Available at: www.hepb.org/professionals/approved_hbv_drugs.htm. Accessed: June 16, 2005.
  • Viral Hepatitis: State of the Art

    1. 1. Viral Hepatitis: State of the Art Rudy Rai, MD Gastroenterology & Hepatology
    2. 2. Human Hepatitis Viruses <ul><li>Enterically Transmitted </li></ul><ul><ul><li>HAV </li></ul></ul><ul><ul><li>HEV </li></ul></ul><ul><li>Percutaneous/ permucosally Transmitted </li></ul><ul><ul><li>HBV </li></ul></ul><ul><ul><li>HCV </li></ul></ul><ul><ul><li>HDV </li></ul></ul><ul><li>Non-Hepatotrophic agents </li></ul><ul><ul><li>SEN </li></ul></ul><ul><ul><li>TTV </li></ul></ul><ul><ul><li>HGV </li></ul></ul><ul><ul><li>? </li></ul></ul>*DNA viruses *RNAViruses
    3. 3. Other agents in Acute Hepatitis (non A-E) <ul><li>CMV </li></ul><ul><li>EBV </li></ul><ul><li>VZV </li></ul><ul><li>HSV </li></ul><ul><li>Parvovirus B19 </li></ul><ul><li>Reovirus </li></ul><ul><li>Mumps </li></ul><ul><li>Yellow fever </li></ul><ul><li>Coxsackie B </li></ul><ul><li>Syncytial Giant cell </li></ul><ul><li>Adenovirus </li></ul><ul><li>Rubella </li></ul><ul><li>Hemorrhagic fevers </li></ul>
    4. 4. Hepatitis A Virus <ul><li>Single strand RNA virus </li></ul><ul><li>Family: Picornaviridae </li></ul><ul><li>Genus: Hepatovirus </li></ul><ul><li>Phases </li></ul><ul><ul><li>Replicative </li></ul></ul><ul><ul><li>Necroinflammatory </li></ul></ul><ul><li>Outcome </li></ul><ul><ul><li>Worse in older patients </li></ul></ul><ul><ul><li>Mild in children </li></ul></ul><ul><ul><li>Superinfection in Hep C (40% mortality) </li></ul></ul>
    5. 5. Hepatitis A: Age Dependent Jaundice <6 6-14 >14 Age in Years Anicteric Icteric
    6. 6. Acute Hepatitis A: Age specific Case Fatality Rates 0-14 15-39 40-49 >50 0.1 0.4 1.1 2.7 Case Fatality Rate (%) Age in Years
    7. 7. Hepatitis A <ul><li>HAV vaccine protects against all human HAV strains </li></ul><ul><li>No reservoir of viremic/intestinal “carriers” </li></ul><ul><li>Infection occurs from acutely infected to susceptibles </li></ul><ul><li>Oral-fecal transmission </li></ul><ul><ul><li>Water </li></ul></ul><ul><ul><li>Food- seafood, mollusks </li></ul></ul><ul><ul><li>Intimate </li></ul></ul><ul><ul><li>Institutional </li></ul></ul><ul><ul><li>Household </li></ul></ul>
    8. 8. Hepatitis A: Sequence Fecal HAV Serum HAV Elevated ALT ! 30 ! 90 ! 60 Days after Exposure IgG IgM
    9. 9. Hepatitis A vaccine: Recommendations ACIP (1999) <ul><li>Community attack rate >20/100,000 </li></ul><ul><ul><li>consider routine childhood vaccination </li></ul></ul><ul><li>High HAV Endemic areas </li></ul><ul><ul><li>Travelers, military, Native Americans </li></ul></ul><ul><li>Outbreaks </li></ul><ul><ul><li>Children/young adults </li></ul></ul><ul><li>Other </li></ul><ul><ul><li>Chronic liver disease </li></ul></ul><ul><ul><li>IDUs </li></ul></ul><ul><ul><li>Men who have sex with men </li></ul></ul><ul><ul><li>Patients with clotting factor disorders </li></ul></ul>
    10. 10. Parvovirus B19 <ul><ul><li>Erythema infectiosum </li></ul></ul><ul><ul><li>Acute Hepatitis </li></ul></ul><ul><ul><li>Fulminant liver failure </li></ul></ul><ul><ul><li>Transient dysfunction </li></ul></ul><ul><ul><li>Aplastic anemia </li></ul></ul>
    11. 11. Herpes Simplex <ul><ul><li>Immunocompromised or pregnant </li></ul></ul><ul><ul><li>Diagnosis: IgM Ab </li></ul></ul><ul><ul><li>Mucocutaneous lesions/ DIC common </li></ul></ul><ul><ul><li>Liver Biopsy: confluent coagulative necrosis, eosinophilic ground-glass inclusions w/clear halo </li></ul></ul><ul><ul><li>Rx: Acyclovir, OLTx </li></ul></ul><ul><ul><li>20-40% survival </li></ul></ul>
    12. 12. Hepatitis E <ul><ul><li>Developing world </li></ul></ul><ul><ul><li>Largely waterborne </li></ul></ul><ul><ul><li>Incubation 6-7 weeks </li></ul></ul><ul><ul><li>Virus shed 2-3 weeks before symptoms </li></ul></ul><ul><ul><li>Transient ALT elevation </li></ul></ul><ul><ul><li>*** Pregnant- Acute Liver Failure </li></ul></ul>
    13. 13. Treatment <ul><li>Hepatitis A and E </li></ul><ul><ul><li>No chronic form </li></ul></ul><ul><ul><li>May need supportive care </li></ul></ul><ul><ul><li>Passive (Immunoglobin) and/or active (Hep A vaccine) immunization for contacts in infectious period </li></ul></ul><ul><ul><li>Recommend preventative vaccine for Hep A w/underlying liver disease* </li></ul></ul><ul><ul><li>Caution for pregnant women traveling to Hep E endemic areas* </li></ul></ul>
    14. 14. Serodiagnosis of Acute Viral Hepatitis <ul><li>Hepatitis A </li></ul><ul><ul><li>HAV IgM </li></ul></ul><ul><li>Hepatitis B </li></ul><ul><ul><li>HBSAg(+); HBCore Ab IgM (+) </li></ul></ul><ul><li>Hepatitis C </li></ul><ul><ul><li>HCV RNA (PCR/TMA); HCV Ab (50-60%) </li></ul></ul><ul><li>Hepatitis D </li></ul><ul><ul><li>HDV Ab IgM; HepBSAg (+)* </li></ul></ul><ul><li>Hepatitis E </li></ul><ul><ul><li>HEV Ab IgM </li></ul></ul>
    15. 15. Model of Human Hepatitis C Virus Lipid Envelope Capsid Protein Nucleic Acid Envelope Glycoprotein E2 Envelope Glycoprotein E1 Reprinted with permission. Henderson, LE. Available at www.hepcprimer.com.
    16. 16. Projected Public Health Burden for HCV <ul><li>The HCV disease burden is projected to peak with an estimated 14,000-19,000 deaths/year </li></ul>Year Deuffic-Burban et al. AASLD; October 24-28, 2003; Boston, MA. Abstract 552. 0 10000 20000 30000 40000 50000 60000 1990 2010 2030 2050 2070 HCV-related mortality, maximal HCV-related mortality, minimal HIV-related mortality, maximal HIV-related mortality, minimal Annual Incidence
    17. 17. Hepatitis C: A Global Health Problem United States 3-4 M Americas 12-15 M Africa 30-40 M Southeast Asia 30-35 M Australia 0.2 M World Health Organization. Weekly epidemiological record. 1999;74:421-428. Western Europe 5 M 170-200 Million (M) Carriers Worldwide Eastern Europe 10 M Far East Asia 60 M
    18. 19. Prevalence of HCV Infection: United States 1990 Alter et al. N Engl J Med . 1999;341:556-562. Anti-HCV+ (%) 0 1 2 3 4 5 6 7 Age (yr) Mexican American Caucasian 3.5% 1.1% African American 3.2% 6–11 12–19 20–29 30–39 40–49 50–59 70+ 60–69
    19. 22. Shiffman et al. J Infect Dis . 2000;182:1595-1601. Elevated ALT Normal ALT Cirrhosis 22% No Fibrosis (KS<5) 19% Inflammation (KS>5) 19% Portal 24% Bridging 16% No Fibrosis (KS<5) 40% Portal 26% Cirrhosis 6% Bridging 6% Inflammation (KS>5) 23% KS, Knodell score. Liver Histology in Patients With Elevated and Normal Serum ALT
    20. 23. Hepatitis C Scenarios <ul><li>HCV Ab </li></ul><ul><li>+ </li></ul><ul><li>- </li></ul><ul><li>+ </li></ul><ul><li>+ </li></ul>HCV RIBA + -/+ - + HCV PCR - + - + Interpretation True Ab, cleared infxn True infxn, Immune deficiency False + Ab, infants Chronic Infxn
    21. 25. Type 1 IFNs: Exhibit Multiple Activities Stark GR, et al. Annu Rev Biochem . 1998;67:227-264. Theofilopoulos AN, et al. Annu Rev Immunol . 2005;23:307-335. Brierley M, et al. J Interferon Cytokine Res. 2002;22:835-845. 0 Many cell types B lymphocytes Immunoregulatory Activity Proliferation, differentiation, activation of different cell types heavily involved in immune responses Natural killer cells T lymphocytes Activation Proliferation Survival Dendritic cells Muscle Fibroblasts Antifibrotic Antiviral Activity Many cell types Adipocytes IFN  /  Antiangiogenic Antiproliferative Activity
    22. 26. Neumann AU, et al. Science . 1998;282:103-107; Dixit NM, et al. Nature. 2004;432:922-924. Biphasic Decline of HCV Load During IFN  -2 b (10 mIU QD) Therapy Viral Load (log 10 HCV RNA eq/mL) Days of Therapy Block in virus production: direct action of ISGs 0 Lag period: 4 – 12 hr (ISG expression) Clearance of infected cells: immune cell modulation Many weeks- months; selection for escape mutants 3 4 5 6 7 1 5 10 14 Ribavirin works in synergy with IFN during phase 2, especially in hard-to-treat patients
    23. 28. <ul><li>Disease acquisition at >40 years </li></ul><ul><li>Male gender </li></ul><ul><li>HIV coinfection </li></ul><ul><li>HBV coinfection </li></ul><ul><li>Fatty liver disease </li></ul>Factors That Speed Progression of Liver Disease Not Within Patient’s Control Hezode et al. EASL; April 14-18, 2004; Berlin, Germany. Abstract 68. Ivanova et al. EASL; April 14-18, 2004; Berlin, Germany. Abstract 484. NIH Consensus Development Conference Statement. Bethesda, Md: National Institutes of Health; June 10-12, 2002. Poynard et al. Lancet. 1997;349:825-832.
    24. 30. <ul><li>ALT </li></ul><ul><li>Viral load </li></ul><ul><li>Mode of transmission </li></ul><ul><li>Genotype </li></ul>Factors That Do NOT Speed Progression of Liver Disease NIH Consensus Development Conference Statement. Bethesda, Md: National Institutes of Health; June 10-12, 2002. Poynard et al. Lancet . 1997;349:825-832.
    25. 31. Role of Liver Biopsy <ul><li>Confirm clinical diagnosis </li></ul>Brunt et al. Hepatology . 2000;31:241-246. Assess severity of necroinflammation Evaluate possible concomitant disease processes Assess therapeutic intervention Assess fibrosis Utility of Liver Biopsy
    26. 32. Hepatic Histopathologic Evaluation <ul><ul><ul><li>Measure of severity and ongoing disease activity </li></ul></ul></ul><ul><ul><ul><li>May fluctuate with disease activity or therapeutic intervention </li></ul></ul></ul><ul><ul><ul><li>Indicates long-term disease progression </li></ul></ul></ul><ul><ul><ul><li>Relatively constant in relation to disease activity or therapeutic intervention </li></ul></ul></ul>Stage Fibrosis Brunt et al. Hepatology. 2000;31:241-246. Grade Necro- inflammation
    27. 33. Progression of Fibrosis on Biopsy No Fibrosis Stage 1: Fibrous expansion of some portal areas Stage 3: Fibrous expansion of most portal areas with occasional portal to portal bridging Stage 4: Fibrous expansion of portal areas with marked bridging (portal to portal and portal to central) Stage 5,6: Cirrhosis, probable or defined Cirrhotic liver: Gross anatomy of cadaver Courtesy of Gregory Everson, MD.
    28. 34. Knodell Ishak METAVIR Absent 0 0 0 Portal fibrosis (some) 1 1 1 Portal fibrosis (most) 1 2 1 Bridging fibrosis (few) 3 3 2 Bridging fibrosis (many) 3 4 3 Incomplete cirrhosis 4 5 4 Cirrhosis 4 6 4 Hepatic Fibrosis Scoring Systems Brunt. Hepatology . 2000;31:241-246.
    29. 35. 0 10 20 30 1 2 3 4 Duration of infection (y) Fibrosis stage SLOW Women <40 years of age Alcohol <50 g/d RAPID Men >40 years of age Alcohol >50 g/d MEDIUM Rates of Fibrosis Progression Marcellin P, et al. Hepatology. 2002;36:S47-S56. 0
    30. 36. Serum Fibrosis Markers Is This a Viable Option to Liver Biopsy? <ul><li>Minimally-invasive algorithmic-based serum marker assays are being evaluated </li></ul><ul><ul><li>HCV FIBROSURE™ (LabCorp ® ) </li></ul></ul><ul><ul><li>FibroSpect SM (Prometheus Laboratories) </li></ul></ul><ul><li>Accurately reflect mild fibrosis </li></ul><ul><li>No utility demonstrated with intermediate fibrosis </li></ul><ul><li>Role in patient management remains controversial </li></ul>Poynard et al. 54th AASLD. October 24 - 28, 2003. Boston, Mass. Abstract 3. Ratziu et al. 39th EASL. April 14-18, 2004. Berlin, Germany. Abstract 597.
    31. 37. Treatment for Hepatitis C
    32. 38. Goals of Antiviral Therapy Viral clearance Prevent HCC Delay decompensation Prevent HCV recurrence after liver transplantation Target the disease Target the virus
    33. 39. Sustained Responder Nonresponder Relapser Nonresponder HCV RNA negative Time (wks) HCV RNA 12 24 48 72 Identifying Nonresponders and Relapsers: HCV Patterns of Response to Therapy Adapted from: Davis GL, et al. Hepatology. 2003;38:645-652. Fried MW, et al. N Engl J Med. 2002;347:975-982. 0
    34. 40. FDA Approved, Marketed HCV Drugs Pawlotsky JM, et al. Hepatology. 2004;39:554-567. *Ribavirin is not approved for monotherapy, but as part of combination with interferon alfa † Interferon relapsers and nonresponders 0.8 – 1.2 g/day, PO 0.8 – 1.2 g/day, PO Copegus ® (Roche) Rebetol ® (Schering-Plough) Ribavirin* 1.0 – 1.5  g/kg QW, SC Peg-Intron ® (Schering-Plough) Peginterferon alfa-2b 180  g QW, SC Pegasys ® (Roche) Peginterferon alfa-2a 9  g TIW, SC 15  g TIW, SC † Infergen ® (InterMune) Interferon alfacon-1 3 MU TIW, SC Intron A ® (Schering-Plough) Interferon alfa-2b 3 MU TIW, SC Roferon-A ® (Roche) Interferon alfa-2a Dosing Name (manufacturer) Product
    35. 41. SVR Rates in HCV Populations AA genotype 1 0 10 20 30 40 50 60 HCV Genotype 1 HVL (all genotypes) Advanced fibrosis and cirrhosis (stages 3 and 4) HIV/HCV HIV/HCV genotype 1 52% - 53% 41% - 44% 42% - 53% 43% - 44% 27% - 40% 17% - 9% 19% - 26% ITT Populations SVR (%) 0 SVR=sustained virologic response; HCV=hepatitis C virus; HIV=human immunodeficiency virus; ITT=intent-to-treat. Torriani FJ, et al. N Engl J Med. 2004;351:438-450. Jeffers LJ, et al. Hepatology. 2004;39:1702-1708. Carrat F, et al. JAMA. 2004;292:2839-2848. Muir AJ, et al. N Engl J Med. 2004;350:2265-2271. Fried MW, et al. N Engl J Med. 2002;347:975-982. Manns MP, et al. Lancet. 2001;358:958-965.
    36. 42. Key HCV Treatment Trials QW, once a week; TIW, three times a week; wks, weeks. Fried et al. N Engl J Med . 2002;347:975-982. Hadziyannis et al. Ann Int Med. 2004;140:346-357. Manns et al. Lancet. 2001;358:958-965. <ul><li>24 vs 48 weeks of therapy (N = 1311) </li></ul><ul><ul><li>PEG IFN 180 μ g + RBV 1000-1200 mg QD </li></ul></ul><ul><ul><li>PEG IFN 180 μ g + RBV 800 mg QD </li></ul></ul>Hadziyannis et al ( 2004) PEG IFN alfa-2a/ RBV 800/1000-1200 <ul><li>48 weeks of therapy (N = 1121) </li></ul><ul><ul><li>PEG IFN 180 μ g + RBV 1000-1200 mg PO QD </li></ul></ul><ul><ul><li>IFN alfa-2b 3 MU SC TIW + RBV 1000-1200 mg PO QD </li></ul></ul><ul><ul><li>PEG IFN 180 μ g SC QW + Placebo </li></ul></ul>Fried et al (2002) PEG IFN alfa-2a/ RBV 1000-1200 <ul><li>48 weeks of therapy (N = 1530) </li></ul><ul><ul><li>PEG IFN 1.5 µ g/kg + RBV 800 mg/day </li></ul></ul><ul><ul><li>PEG IFN 1.5 µ g/kg (4 wks), then 0.5 µ g/kg (44 wks) + RBV 1000-1200 mg/day </li></ul></ul><ul><ul><li>IFN alfa-2b 3 MU TIW + RBV 1000-1200 mg/day </li></ul></ul>Manns et al (2001) PEG IFN alfa-2b/ RBV 800
    37. 45. HCV RNA Structure Structural Non-Structural Structure Processing Replication 5 ' UTR IRES, Translation Transcription, Replication IRES = internal ribosomal entry site; UTR = untranslated region; C = nucleocapsid core; E1 = envelope protein 1; E2 = envelope protein 2; NS = non-structural Hoofnagle JH. Hepatology. 2002;36(5 suppl 1):S21-S29. 3 ' UTR C E1 E2 Nucleocapsid, Assembly Envelope Proteins, Assembly and Entry p7 Calcium Channel? NS2 NS3 NS4A Protease Serine Protease, Helicase NS3 cofactor NS4B NS5A NS5B Replication? Phosphoprotein, Replication RNA-dependent RNA polymerase
    38. 46. Potential HCV Therapies R803 Rigel Amantadine Endo Labs Solvay Multiferon Viragen Omega IFN Biomedicine ISIS 14803 Isis ANA245 ANADYS Albuferon Human Genome Sciences VX-950 Vertex HCV-086 ViroPharma/ Wyeth Phase III Phase II Phase I Viramidine Valeant Zadaxin SciClone Infergen/gamma IFN InterMune Oral IFN alpha Amarillo Biosciences NM283 Idenix JTK 003 AKROS Pharma HCV/MF59 Chiron SCH-6 Schering Civacir NABI HepX-C XTL IDN-6556 Idun VX-497 Vertex Ceplene Maxim Time to Market E-1 Innogenetics IP-501 Indevus REBIF Ares-Serono
    39. 47. Side Effects of Interferon <ul><li>Flu-like symptoms </li></ul><ul><ul><li>Headache </li></ul></ul><ul><ul><li>Fatigue or asthenia </li></ul></ul><ul><ul><li>Myalgia, arthralgia </li></ul></ul><ul><ul><li>Fever, chills </li></ul></ul><ul><li>Neuropsychiatric disorders </li></ul><ul><ul><li>Depression </li></ul></ul><ul><ul><li>Mood lability </li></ul></ul><ul><li>Alopecia </li></ul><ul><li>Thyroiditis </li></ul><ul><li>Nausea </li></ul><ul><li>Diarrhea </li></ul><ul><li>Injection-site reaction </li></ul><ul><li>Lab alterations </li></ul><ul><ul><li>Neutropenia </li></ul></ul><ul><ul><li>Anemia </li></ul></ul><ul><ul><li>Thrombocytopenia </li></ul></ul>
    40. 48. Side Effects of Ribavirin <ul><li>Hemolytic anemia </li></ul><ul><li>Teratogenicity </li></ul><ul><li>Cough and dyspnea </li></ul><ul><li>Rash and pruritus </li></ul><ul><li>Insomnia </li></ul><ul><li>Anorexia </li></ul>Rebetron  [package insert]. Kenilworth, NJ: Schering Corp; 2002.
    41. 49. Predictors of SVR <ul><li>Gt 2 </li></ul><ul><ul><li>Gt 3 more difficult to treat than Gt 2 </li></ul></ul><ul><li>Low baseline viral load </li></ul><ul><li>Early virologic response, Week 12-24 </li></ul><ul><ul><li>Modifiable through adherence </li></ul></ul><ul><li>Absence of cirrhosis </li></ul><ul><li>Female gender </li></ul><ul><li>Aged  40 years </li></ul><ul><li>Low hepatic iron stores </li></ul><ul><li>Short duration of disease (<5 years) </li></ul>Fried et al. N Engl J Med . 2002;347:975-982. Hadziyannis et al. Ann Int Med . 2004;140:346-357. Mangia et al. EASL; April 14-18, 2004; Berlin, Germany. Abstract 93. Manns et al. Lancet. 2001;358:958-965. McHutchison et al. Hepatology. 2000;32:223A. Poynard et al. Hepatology . 2000;31:211-218. Zeuzem et al. N Engl J Med . 2000;342:1666-1672.
    42. 50. Summary <ul><li>Hepatitis C is a complex but treatable disease </li></ul><ul><li>Early identification is key </li></ul><ul><li>Normal ALT does not equal mild or no disease </li></ul><ul><li>Treatment modalities are rapidly evolving </li></ul>
    43. 51. Hepatitis B
    44. 52. Chronic Hepatitis B <ul><li>Tenth leading cause of death worldwide </li></ul><ul><li>400 million worldwide </li></ul><ul><li>1.25 million in the US </li></ul><ul><ul><li>4 million in Western Europe </li></ul></ul><ul><ul><li>80% of HBV carriers in Asia </li></ul></ul><ul><li>4,000 to 5,500 deaths annually in the US </li></ul><ul><li>In ~30% of patients with chronic HBV </li></ul><ul><ul><li>Infection, cirrhosis or HCC will develop </li></ul></ul>
    45. 53. Hepatitis B – Historical perspective MMWR. 2004;52:1252-1254. HepB.Org . Available at: www.hepb.org/professionals/approved_hbv_drugs.htm. Accessed: June 16, 2005. <ul><li>Vaccine recommended for adults and adolescents with significant risk factors </li></ul><ul><li>Mass immunizations implemented in infants, pregnancy screening, infant post-exposure perinatal prophylaxis </li></ul><ul><li>Lamivudine first oral therapy approved </li></ul><ul><li>Adefovir approved </li></ul>2005 <ul><li>E ntecavir approved </li></ul><ul><li>Peginterferon alfa-2a injectable approved </li></ul><ul><li>α -interferon injection first treatment for hepatitis B approved </li></ul>1982 1991 1998 2002 Year
    46. 54. Questions Asked Before Treating <ul><li>Who do I treat? </li></ul><ul><li>HBV DNA (+) </li></ul><ul><li>HBeAg (+) or (-) </li></ul><ul><li>Elevated ALT or AST </li></ul><ul><li>Liver biopsy evidence of chronic hepatitis </li></ul><ul><li>What do I use? </li></ul><ul><li>Nucleoside? Which? </li></ul><ul><li>Interferon? </li></ul><ul><li>Combination therapy ? </li></ul>
    47. 55. Nucleoside Analogues Pros Cons Oral administration Long duration of treat- ment ( > 1 yr )“virustatic” Minimal side effects Drug-resistant mutants Useful in decompensated Type of response differs c irrhosis and post-OLT from IFN (HBsAg loss rare) Much less expensive Post-withdrawal ALT than IFN flares ( ~20-25%)
    48. 56. Incidence of Lamivudine Resistance in Chronic HBV Infection Percent Lamivudine Resistant Resistance > HBeAg loss Years of Lamivudine 90% HIV- Pos 53% 20% 49% 67% 38% 0% 20% 40% 60% 80% 1 2 3 4
    49. 57. Chronic Hepatitis B Treatment Options <ul><li>Interferon/ PEG IFN- FDA approved Jul 2005* </li></ul><ul><li>Nucleoside Analogues </li></ul><ul><ul><ul><ul><li>Lamivudine </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Adefovir </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Entecavir - FDA approved in Mar 2005 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Emtricitabine ** </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Tenofovir ** </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Telbivudine - Phase III enrollment completed </li></ul></ul></ul></ul>** Off label use
    50. 58. Questions? Thank You for your attention!

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